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Science. 2017 Dec 22;358(6370):1617-1622. doi: 10.1126/science.aan6414. Epub 2017 Nov 30.

Synthetic transcription elongation factors license transcription across repressive chromatin.

Author information

1
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
4
Genomics and Molecular Medicine, Council of Scientific and Industrial Research (CSIR)-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India.
5
Novartis Institutes for BioMedical Research (NIBR), Cambridge, MA 02139, USA.
6
Department of Dermatology, University of Wisconsin-Madison, Madison, WI 53706, USA.
7
Small Animal Imaging Facility, University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA.
8
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA. azansari@wisc.edu.
9
The Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706, USA.

Abstract

The release of paused RNA polymerase II into productive elongation is highly regulated, especially at genes that affect human development and disease. To exert control over this rate-limiting step, we designed sequence-specific synthetic transcription elongation factors (Syn-TEFs). These molecules are composed of programmable DNA-binding ligands flexibly tethered to a small molecule that engages the transcription elongation machinery. By limiting activity to targeted loci, Syn-TEFs convert constituent modules from broad-spectrum inhibitors of transcription into gene-specific stimulators. Here we present Syn-TEF1, a molecule that actively enables transcription across repressive GAA repeats that silence frataxin expression in Friedreich's ataxia, a terminal neurodegenerative disease with no effective therapy. The modular design of Syn-TEF1 defines a general framework for developing a class of molecules that license transcription elongation at targeted genomic loci.

PMID:
29192133
PMCID:
PMC6037176
[Available on 2018-12-22]
DOI:
10.1126/science.aan6414
[Indexed for MEDLINE]

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